Idiopathic membranous nephropathy (IMN) is an autoimmune disease of the kidney and a common cause of the nephrotic syndrome in adults. In addition to the weight gain, swelling, and risk of blood clots that accompany this disease, a substantial fraction of patients will develop progressive loss of kidney function and require dialysis or transplantation. Treatment for IMN often requires toxic immunosuppressive agents, which themselves cause health problems and risk of serious infection. The questions of who, when, and how long to treat have been difficult to answer due to an incomplete understanding of which patients will undergo remission from this disease on their own and who will progress to end-stage kidney disease. The recent identification by our laboratory of circulating antibodies that target a kidney protein, the phospholipase A2 receptor (PLA2R), in the majority of patients with IMN has not only allowed a redefinition of IMN based on these autoantibodies, but has also provided a potential mechanism by which to monitor the immunologic activity of the disease and guide these often-difficult treatment decisions. This proposal outlines our plans to use samples and data sets from the 150 patients with IMN to be enrolled in NEPTUNE (Nephrotic Syndrome Study Network) to better characterize the newly-recognized subgroups of IMN. Aim 1 will classify each of the 150 IMN patients into two subgroups based on the presence of anti-PLA2R antibodies in the bloodstream or the presence of the PLA2R antigen within immune deposits of biopsy tissue already collected for this study. This will stratify the cohort into anti-PLA2R-associated or anti-PLA2R-negative disease. We will use the extensive NEPTUNE data sets of baseline demographic and clinical data, as well as the precise features seen in the biopsies of these patients, to find features that distinguish these two subtypes of IMN. A second portion of this aim will examine anti-PLA2R levels over time and use this information to follow immunological disease activity and thereby define 'immunological remission.' We will use the data from this aim to validate our hypothesis that immunological activity as reflected by the level of anti-PLA2R occurs prior to the clinical response, and may be a better measure of disease activity in general. Aims 2 and 3 will harness the powerful gene transcription data sets available from the NEPTUNE cohort of IMN patients. Aim 2 seeks to define anti-PLA2R-associated transcriptional networks in biopsy tissue in order to better understand molecular mechanisms of disease in IMN. Aim 3 is designed to identify gene expression profiles that can functionally define and predict immunological remission, using gene expression data sets collected from circulating blood cells as well as the baseline kidney biopsy tissue. In aggregate, this project wil generate data that (1) defines and fully characterizes anti-PLA2R-associated IMN, (2) establishes the definition of immunological remission and its relationship to clinical remission, and (3) defines descriptive and predictive gene pathways that will greatly impact our future understanding of membranous nephropathy.